Two independent studies have been developed in this thesis. In the first study, the reactivities of metal-alkoxide and metal-hydroxide nucleophiles are compared for cleaving phosphate diesters. In the second study, the reactivity of a dinuclear metal complex is compared to a mononuclear metal complex for hydrolyzing RNA. / Copper(II) complexes of bis(2-pyridylmethyl)amine (Cu(II)bpa), N-(2-hydroxyethyl)bis(2-pyridylmethyl)amine (Cu(II)hebpa) and N-(3-hydroxypropyl)bis(2-pyridylmethyl)amine (Cu(II)hpbpa) have been synthesized and their reactivities and mechanisms for cleaving bis(2,4-dinitrophenyl) phosphate (BDNPP) have been investigated. Cu(II)hpbpa is observed to be the most reactive (k = 7.2 $ times$ 10$ sp{-1}$ M$ sp{-1}$ s$ sp{-1}$ at 25$ sp circ$C, pH 8.8) for cleaving BDNPP followed by Cu(II)bpa (k = 2.0 $ times$ 10$ sp{-2}$ M$ sp{-1}$ s$ sp{-1}$) and Cu(II)hebpa (k = 2.0 $ times$ 10$ sp{-2}$ s$ sp{-1}$). HPLC product analyses indicated that Cu(II)hpbpa cleaves BDNPP mostly through transesterification while the complexes Cu(II)bpa and Cu(II)hebpa cleave BDNPP predominantly by hydrolysis. The differences in the mechanisms and the reactivities are explained in terms of the differences in the structures of the three copper(II) complexes. / Copper(II) complexes of 1,8-bis(1,4,7-triazacyclononyl-N-methyl)naphthalene (tntn), 1,4,7-triazacyclononane (tacn), and N-benzyl-1,4,7-triazacyclononane (btacn) have been prepared and their reactivities compared for cleaving RNA. The novel dinuclear copper(II) complex, Cu(II)$ sb2$tntn, is observed to be 200-500 fold faster per metal center than the mononuclear copper(II)complexes, Cu(II)tacn and Cu(II)btacn, for cleaving a diribonucleotide, ApA, and its cyclic phosphate intermediate, $2 sp prime3 sp prime$-cAMP. Cu(II)$ sb2$tntn (2.0 mM) reduces the half life of ApA (0.05 mM) to 50 minutes (pH 6, 50$ sp circ$C); this represents a rate acceleration of approximately 10$ sp5$ fold over the background hydroxide rate. The half life of $2 sp prime3 sp prime$-cAMP (0.05 mM) is decreased to 4 minutes in the presence of Cu(II)$ sb2$tntn (2.0 mM, pH 6, 25$ sp circ$C); this represents a rate acceleration of about 10$ sp8$ fold over the background hydroxide rate.

A series of hindered biphenols specifically designed to form stable biphenoxy radicals were prepared by an oxidative coupling reaction of hindered phenols in the presence of CuCl and molecular oxygen in butyronitrile or by reacting the diphenoquinones with HCl gas. / The biphenoxy radicals generated from the oxidation of the original biphenols with an aqueous solution of KOH/K$ sb3$Fe(CN)$ sb6$ or Ag$ sb2$O were used as reagents in organic reactions and catalysts in the oxidation of diarylmethanes to corresponding ketones. They were also used in the synthesis of novel ether and acetal monomers through a quantitative radical coupling reaction with monomers containing activated methylene groups. These ether and acetal compounds were readily cleaved under acidic conditions thus providing a new method of cleaving benzylic and t-butyl ethers under mild conditions and for functionalizing activated methylene groups. To simplify the purification steps biphenol A6.19 was incorporated into the backbone of a poly(aryl ether) chain and used as a polymeric support material. / The quantitative radical coupling reaction and cleavage of the resulting ethers and acetals led to the synthesis of novel carbon - oxygen coupled polymers that could potentially be used as photoresist materials since they are cleaved to low molecular weight organic compounds in the presence of acid. / In part B a new mass spectrometry technique, Matrix Assisted Laser Desorption Ionization-Time of Flight, was examined as a potential tool in determining the absolute molecular weight, sequence distribution, and end groups of low molecular weight polydisperse polymers and cyclic oligomers.

Organometallic reactions, including allylation, alkylation, aldol and Reformatsky type reactions of carbonyl compounds in aqueous media mediated by Sn, Zn, Mn, and In were studied. The possible mechanism and stereochemistry of these reactions were investigated. The methodology has successfully been applied to the syntheses of 1,3-butadienes, vinyloxiranes, and methylenetetrahydrofurans; and the syntheses of natural product (+)-muscarine, (+)-epimuscarine, (+)-KDN and (+)-KDO. / A novel tellurium reagent, bis(triphenylstannyl)telluride, for organic synthesis was developed. Its application in the preparation of organotellurium compounds, reduction of vic-dihalides and $ alpha$-halo ketones, desulfurization of organic trisulfides and cleavage of organic disulfides was studied. All the reactions with this reagent proceeded under very mild conditions.

A general strategy for the synthesis of phospholipids was developed. The method was demonstrated using 3-O-allyl-sn-glycerol 33 which was regiospecifically converted to 1-palmitoyl-2-(5-O-TBDMS-stearoyl)-3-O-allyl-sn-glycerol 43 by the sequential acylation of the primary and secondary hydroxyls. The allyl group was removed in two steps by isomerization to a vinyl ether and hydrolysis with N-bromosuccinimide in aqueous tetrahydrofuran. A new method for the conversion of the 1,2-diacylglycerols to phosphatidylcholines under acid-catalyzed conditions was developed. The diacylglycerols were treated with (2-bromoethyl)-($ 2$-cyanoethyl)-(N,N-diisopropylamino)-phosphoramidite 51 in the presence of tetrazole as catalyst, the phosphite triester was oxidized, and the neutral phosphate triester was treated with trimethylamine to simultaneously deprotect the phosphate and convert the bromoethyl substituent to the choline function. A modification was introduced to extend the synthetic strategy to unsaturated phosphatidylcholines. The starting material was 3-(4-methoxybenzyl)-sn-glycerol 30 (3-PMB-sn-glycerol). Diacylation of the hydroxyls with 13-tetradecynoic acid 64a followed by Glaser oxidation gave 1,2-(13,15-octacosadiyn-1-28-dioyl)-3-PMB-sn-glycerol 66. The 4-methoxybenzyl ether was cleaved using bromodimethylborane at $-$78$ sp circ$C in methylene chloride. The diacylglycerol 67 was converted to the phosphatidylcholine as before. Sequential acylation of 30 with palmitic acid and 15-hexadecynoic acid 64b followed by Glaser oxidation gave 2,2$ sp prime$-(15,17-dotriacontadiyn-1,32-dioyl)-bis- (1-palmitoyl-3-PMB-sn-glycerol) 72, which was converted to the bis-phosphatidylcholine 75 in the same manner as 66.

Order-disorder phase transitions in solid cyclopentene, cyclohexene, tetramethylene sulfoxide, pentamethylene sulfide, cycloheptane, cycloheptene, 1,3-cycloheptadiene and 1,3,5-cycloheptatriene, were studied by various combinations of differential scanning calorimetry, proton spin-lattice relaxation time measurements, and variable temperature infrared and Raman spectroscopy. / Possible unit cell symmetries have been proposed for the low temperature phases of several of these compounds, based on splitting observed in the vibrational spectra. The high temperature phases of cyclopentene, cyclohexene and 1,3-cycloheptadiene, for which the flexibility of the ring is reduced relative to the saturated analogues due to the presence of one or more double bonds, were found to be characterized by anisotropic molecular reorientation, as opposed to the other compounds, in which isotropic reorientation occurred. The ring puckering vibrations, when observed, were found to undergo significant frequency shifts at the order-disorder transitions. "Glassy crystals" were readily formed from cyclohexene, cycloheptane, cycloheptene, and 1,3-cycloheptadiene, the spectra of which confirmed the presence of static disorder related to the disorder present in their respective high temperature phases. / Phase transitions in cyclohexane and cyclohexane-d$ sb{12}$ at high pressure were investigated by infrared and Raman spectroscopy using diamond anvil cells. Two phase transitions were observed in cyclohexane at 5.1 and 9.6 kbar, respectively. The vibrational spectra indicated that the change in unit cell symmetry was from O$ sb{ rm h}$ to D$ sb{ rm 2h}$ at the first transition, and then to C$ sb{ rm 2h}$ at the second transition. A study of the C-H oscillators of cyclohexane-d$ sb{11}$, dilute in cyclohexane-d$ sb{12}$, confirmed these changes in unit cell symmetry.

Pseudomonas cepacia lipase (PCL) is a highly enantioselective catalyst in the hydrolysis or formation of esters. It shows high enantioselectivity towards esters of chiral primary alcohols. Several scientists have tried to explain this enantioselectivity via modelling studies, however their results are in disagreement. / To explain PCL enantioselectivity towards chiral primary alcohols, we coupled structural studies and modelling of PCL-transition state analogue complexes containing pure enantiomers of chiral primary alcohols as alcohol moieties. / We first elucidate the different enantiospecificity of the enzyme for primary and secondary alcohols showing that primary alcohols do not bind to PCL like secondary alcohols. We then show that PCL enantioselectivity towards 3-methyl-2-phenyl-1-propanol, a chiral primary alcohol without oxygen at the stereocentre, rests on the better hydrogen bond of the fast enantiomer with catalytic histidine and that there are only subtle binding differences between the two alcohol enantiomers within the catalytic pocket of PCL. / Next, we show that PCL enantioselectivity towards chiral primary alcohols having oxygen at the stereocentre depends mainly on the interaction of the oxygen at the stereocentre with PCL residues Leu17 and Thr18, which may favour or disfavour one enantiomer depending on its structural features. This explains why a simple empirical rule cannot be reliably applied to this class of substrates. / We then exploit PCL interfacial activation and the use of a solvent that stabilises the active open form of the enzyme to increase its enantioselectivity towards esters of 2-methyl-3-phenyl-l-propanol and 2-phenoxy-l-propanol from 16 to ≥190 and from 17 to 70. / Last, we try to increase the enantioselectivity of Bacillus thermocatenulatus lipase (BTL2) towards solketal-n-octanoate and some other chiral primary alcohols by structure-guided saturation mutagenesis. However most of the mutants were inactive and we did not find a more enantioselective BTL2 mutant. / Overall, we have shown that lipase enantioselectivity towards chiral primary alcohols is always based on subtle enzyme-substrate interactions, hence the difficulty to increase lipases enantioselectivity towards these substrates by substrate and protein engineering.

Chapter one of this thesis reviews some work on cubane, from its initial synthesis by Eaton in 1964, to the recent studies of explosive and medicinal applications. Considering the wide variety of compounds that have been synthesized, it is curious that sulfur functionalized cubane has received virtually no attention. / Chapter two discusses the synthesis of cubanethiol, dicubyl disulfide, and a range of derivatives. Dicubyl disulfide possesses the shortest C-S bond length of any reported molecule where the carbon is sp3 hybridized. Calculations have confirmed that this apparently results from the high s-character that the external bonds of cubane possess. All four of the stable, oxidized versions of dicubyl disulfide have been prepared, as well as two trityl cubyl polysulfides. / In Chapter three, new synthetic pathways for the synthesis of cubylcarbinol have been established. One key step is the "two-in-one reaction" that performs the reduction of the carboxylic acid, as well as dehalogenation of 4-iodocubanecarboxylic acid using a single reagent to afford cubylcarbinol. This pathway increases the overall yield for obtaining cubylcarbinol, as well as being more economical. / Chapter four describes the work carried out on cubane-containing dialkoxy disulfides. The synthesis of two dialkoxy disulfides from cubylcarbinols was accomplished. The S2 liberation ability of these species was also investigated, and these represent the first non-benzylic dialkoxy disulfides that deliver trappable S2. In addition, a study of the previously unknown rearrangement/oxidation of these molecules to sulfites has been carried out. / In Chapter five, a thorough study of the reactivity of a vinyl cubane compound towards polymerization was performed. The subsequent cage opening and rearrangement to a styrene derivative, to our knowledge, is the first example of this kind known to occur without the assistance of a rhodium catalyst. In addition, cubane-containing norbornene polymers have been successfully synthesized. These represent the first examples of polymers that have a cubane tethered to the polymer backbone. It appears that this type of functionality does not impair solubility, which is the major problem associated with all other attempts to obtain cubane-based polymers.

This thesis describes an investigation on the synthesis of chiral 1,2,3,4-tetrahydroisoquinoline-based amino alcohols (THIQNOLs) and their use as chiral ligands. / The synthesis of these structures using an aza-Friedel-Crafts reaction between 3,4-dihydroisoquinoline and naphthols is described in the first part of the thesis. By design, this process occurs without added catalyst and serves as a proof of concept for greener (or self-catalytic) catalysis. The reactions can be carried out either in absence of solvent or by using water as solvent. / The second part of this thesis describes the synthesis of optically enriched THIQNOLs for their use as chiral ligands. The first generation of ligands is a set of tertiary amino alcohols, which were applied to the asymmetric addition of diethylzinc to aldehydes. The second generation of ligands is a set of secondary amino alcohols and these were also applied to the asymmetric addition of diethylzinc to aldehydes, improving on the results achieved with the first generation. / La présente thèse a pour but, l'étude de la synthèse des composés de type 1,2,3,4-tetrahydroisoquinoline portant une fonctionnalité amino-alcool (THIQNOLs). Grâce à cette fonctionnalité, il est possible d'utiliser ces composés comme ligands chiraux en synthèse asymétrique. / La première partie de la thèse décrit la synthèse racémique de ces composés en utilisant la réaction aza-Friedel-Crafts entre les 3,4-dihydroisoquinolines et les naphthols. Ce procédé ne nécessite ni catalyseur, ni réactif stochiométrique. Cette réaction sert de preuve de concept qu'une catatyse plus ''verte'' (ou auto-catalysée) est possible. En général, ces réactions ne nécessitent pas de solvant, bien que l'eau peut être utilisée. / La seconde partie de la thèse décrit la synthèse asymétrique des composés THIQNOLS ainsi que leur utilisation en tant que ligand chiraux pour l'addition asymétrique du diethylzinc aux aldehydes. La première génération des ligands est basée sur les amino-alcool tertiaires, alors que la deuxième génération repose sur les amino-alcool secondaires. Les résultats obtenus pour les ligands de la deuxième génération sont, en général, supérieur à ceux de la première génération.

A series of studies on 2'-fluorinated and 4'-chalcogen-modified nucleic acids is described, mainly directed toward the development of better gene silencing therapeutics. NMR/MD and osmotic stressing were used to compare the structure and hydration of 10-bp 2'F-ANA:RNA, ANA:RNA and DNA:RNA duplexes. The 2'F-ANA and ANA strands both featured sugars that pucker in the east (O4'-endo) conformation, as previously observed for hairpin structures containing hybrid stems. Osmotic stressing suggested that the 2'F-ANA:RNA duplex liberated fewer molecules of water upon melting than did ANA:RNA, which may give the former an entropic advantage that contributes to its far greater thermal stability. The stability of 2'F-ANA to acid-mediated hydrolysis was compared to that of DNA and RNA. Several phosphodiester (PO) or phosphorothioate (PS) 2'F-ANA sequences were incubated at pH ~1.2, and virtually no cleavage was observed after 2 days. In contrast, rapid degradation was observed for DNA (t1/2 = minutes) and RNA (t1/2 = hours (PO) or days (PS)). The nuclease-catalyzed hydrolysis of 2'F-ANA was also explored in detail. One diastereomer of the PS-2'F-ANA linkage was much more vulnerable to enzymatic cleavage than the other, which is parallel to the properties observed for PS-DNA. We also show that the nuclease stability induced by 2'F-ANA depends on the oligonucleotide sequence. An improved synthesis of 2'-deoxy-2'-fluoro-5-methyl-4'-thioarabinouridine (4'S-FMAU) is described. Participation of the 3'-O-benzoyl protecting group in the thiosugar precursor influenced the stereochemistry of the N-glycosylation reaction in nonpolar solvents, permitting a higher beta/alpha ratio than previously observed for similar Lewis acid-catalyzed glycosylations. The nucleoside adopted a predominantly northern conformation, in contrast to 2'-deoxy-2'-fluoro-5-methylarabinouridine (FMAU), which adopts a predominantly southeast conform / On a fait une série d'études sur des acides nucléiques contenant un 2'-fluor et/ou un 4'-chalcogène. Ces études visent l'amélioration de thérapeutiques basées sur le silençage des gènes.On a utilisé la RMN/DM et le stressage osmotique pour comparer la structure et l'hydratation des duplex 2'F-AAN:ARN, AAN:ARN et ADN:ARN. Les sucres des brins de 2'F-AAN et d'AAN adoptent la forme O4'-endo (est), comme observé dans le passé. Le stressage osmotique a suggéré que la fusion du duplex 2'F AAN:ARN a libéré moins de molécules d'eau que celle du duplex AAN:ARN, ce qui pourrait donner à ce premier un avantage entropique qui contribue à sa stabilité beaucoup plus élevée. On a comparé la stabilité du 2'F-AAN envers l'hydrolyse par acide à celle de l'ADN et de l'ARN. Plusieurs oligonucléotides en PO ou PS ont été incubés à pH ~1.2, et il n'y avait pas de clivage pour le 2'F-AAN après deux jours. Par contre, on a observé une dégradation rapide pour l'ADN (t1/2 = minutes) et l'ARN (t1/2 = heures (PO) ou jours (PS)). On a exploré aussi l'hydrolyse du 2'F-AAN par nucléase en détail. Un diastéréoisomère de la liaison PS-2'F-AAN a été beaucoup plus vulnérable au clivage par l'enzyme que l'autre, ce qui est parallèle aux propriétés du PS-ADN. Nous démontrons aussi que la stabilité introduite par le 2'F-AAN dépend de la séquence de l'oligonucléotide.On décrit une synthèse améliorée du 2'-désoxy-2'-fluoro-5-méthyle-4'-thioarabinouridine (4'S-FMAU). Une participation par le groupe 3'-O-benzoyl influence la stéréochimie de la N-glycosylation dans des solvants non-polaires. Ceci a permis un plus haut rapport des produits beta/alpha que celui qui a été observé dans le passé pour des glycosylations semblables catalysés par acide Lewis. Le nucléoside adopte une forme nord, tandis que le 2'-désoxy-2'-fluoro-5-méthyle-arabinouridine (FMAU) adopte principalement une

Recently, organometallic reactions in aqueous media have received considerable attention in organic synthesis because of environmental and economical concerns and synthetic efficiency. In this connection, the synthetic utility of environmentally benign non-toxic bismuth metal for aqueous organometallic reactions is investigated. Bismuth metal activated by ammonium hydrogen fluoride can efficiently reduce a wide variety of alpha-halocarbonyl compounds in aqueous media to provide the corresponding dehalogenated reduction products in excellent yields. Zinc fluoride is also found to be effective in activating bismuth to mediate the crossed aldol type reactions of diverse alpha-bromocarbonyl compounds with aldehydes in aqueous media to afford the corresponding beta-hydroxycarbonyl compounds in moderate to high yields. The scope of bismuth-mediated aqueous organometallic reactions is successfully extended to the Reformatsky type reactions. The factors that affect the reactivity of these reactions are examined and plausible reaction mechanisms are proposed.